Endotoxin Recognition Molecules MD-2 and Toll-like Receptor 4 as Potential Targets for Therapeutic Intervention of Endotoxin Shock

Gram-negative sepsis is the major cause of deaths in intensive care units of hospitals and continues to increase worldwide due to the increased frequency of invasive procedures and therapy leading to immunosuppression. This syndrome is characterized by endothelial damage, coagulopathy, loss of vascular tone, tissue hypoperfusion, and multiple-organ failure. They are caused by uncontrolled, overwhelming inflammatory responses, which are triggered by microbial products. Amongst these products, endotoxin also called LPS (lipopolysaccharide), a constituent of the outer membrane of Gram-negative bacteria, is known to play a central role by eliciting immune responses leading to production of proinflammatory cytokines. Our understanding of LPS recognition has increased dramatically over the last several years by identification of Toll-like receptor 4 (TLR4) and MD-2 as LPS recognition molecules. TLR4 is a mammalian homologue of drosophila Toll. The extracellular domain of TLR4 is associated with a molecule called MD-2. Mice lacking either TLR4 or MD-2 do not respond to LPS and are resistant to endotoxin shock. Here, the potential for TLR4-MD-2 as target molecules for therapeutic intervention is discussed.